Brain rescue instrument and method

ABSTRACT

An intelligent brain rescue instrument for identifying, monitoring, and guiding the application of brain therapies to patients with evolving brain injuries, comprises an input for acquiring a multiple number of signals each indicative of a different biochemical or biophysical parameter of a patient, and a computer to continuously sample each of the acquired signals and display to a user on a monitor at least some of the parameters. The displayed parameters are selected by system software embodying expert analytical rules as the most significant parameters, or as parameters having values indicative, or predictive at any time of actual, or potential future deterioration of the brain state of the patient.

This application is a continuation of application Ser. No. 09/445,760filed on Feb. 18, 2000.

FIELD OF INVENTION

This invention relates particularly to data evaluation equipment andprocedures for the monitoring and management of brain injuries inmammals.

BACKGROUND

The brain can be compromised by a number of adverse influences duringall stages of life including perinatal asphyxial and hypoperfusioninsults, strokes, traumatic brain injuries, cardiac arrest, cardiacbypass surgery, poisoning, and subarachnoid haemorrhages. Considerablevariation occurs in the degree and distribution of neuronal lossdepending on the type and severity of the injury to the brain.

Injury results in two recognised phases of neuronal loss (see FIG. 16 ofthe accompanying figures): primary neuronal death is associated with theinsult itself, and delayed neuronal death occurs during a secondaryphase some hours later, when a complex pathological cascade of eventsleading to neuronal death follows the initial injury. A transientinsult, such as hypoperfusion, can cause brain cells to die in twophases. The primary phase extends throughout the insult and the earlyregeneration/reperfusion period. Processes contributing to this primaryphase include intracellular Na⁺ and Ca²⁺ accumulation, cytotoxic edema,membrane damage, free radicals, and excitotoxicity. However, manyneurons do not necessarily die during the primary phase but cytotoxicmechanisms are triggered that lead to a further or delayed death ofneurons some hours later. The mechanisms involved in delayed neuronaldeath are thought to include excitoxicity, seizures, apoptosis, andmicroglial activation.

Recent studies suggest that it is possible to interfere with thesemechanisms and thereby rescue susceptible neurons. Biophysical measuresof the pathophysiologic processes preceding and during the phases ofneuronal death are likely to prove useful for identifying those patientswho may benefit from neuronal rescue therapies. Several clinicallyrelevant factors such as pre-existing injuries, hypotension or metabolicstatus may sensitise and alter the response of the brain to injury.Several biophysical parameters recorded during and after an insult aregenerally needed to reliably discriminate the present phase of injuryand periods of cytotoxic activity.

The monitoring of patients with brain injuries whether caused byexternally induced trauma such as birth or accident or by circulatoryproblems or poisoning has hitherto relied upon clinical signs but thesemay not be observable until a time at which the damage may have becomeirreversible. Neurological examination is of limited value (inparticular for those on life support apparatus) for predicting outcomeand determining the phase of injury. Similarly, use of imagingtechniques such as MRI and CT are not practical for monitoring evolvinginjuries in these patients.

SUMMARY OF INVENTION

The invention provides an intelligent monitoring instrument, termed abrain rescue instrument or monitor, and method, for monitoring,identifying and guiding the application of brain therapies to patients,with evolving brain injuries, and generally for assisting with themanagement and treatment of brain injury in a mammalian patient.

In broad terms in one aspect the invention comprises an intelligentbrain rescue instrument for identifying, monitoring, and guiding theapplication of brain therapies to patients with evolving brain injuries,comprising:

input means for acquiring a multiple number of signals each indicativeof a different biochemical or biophysical parameter of a patient, and

computing means configured to continuously sample and process each ofthe acquired signals and display to a user on a monitor at least some ofthe parameters, the displayed parameters being selected by systemsoftware embodying expert analytical rules as the most significantparameters or as parameters having values indicative or predictive atany time of actual or potential future deterioration of the brain stateof the patient.

In broad terms in another aspect the invention comprises an intelligentbrain rescue instrument for identifying, monitoring, and guiding theapplication of brain therapies to patients with evolving brain injuries,comprising:

I) input means for acquiring a set of a multiple number of signals eachindicative of a different biochemical or biophysical parameter of thepatient, said set of signals being selected from:

(a) an EEG signal;

(b) an ECG signal;

(c) a signal indicative of brain tissue impedance of the patient;

(d) signal or signals indicative of the temperature of the patient;

(e) signals indicative of the arterial blood pressure and/or arterialoxygen saturation, of the patient;

(f) a signal indicative of intracranial pressure;

(g) a signal or signals indicative of any of cerebral blood flow,cerebral blood volume, cerebral oxygenation, or cerebral metabolitemeasures;

(h) a signal or signals indicative of systemic glucose concentrationand/or central glucose concentration;

(i) a signal or signals indicative of systemic lactate concentrationand/or central lactate concentration;

(j) a signal indicative of cerebrovascular status;

(k) a signal indicative of cerebral cytochrome levels;

(l) a signal indicative of the patient's heart rate;

(m) a signal indicative of central cytotoxic activity;

(n) a signal or signals indicative of movement or muscle activity;

(o) a signal or signals indicative of any other biochemical orbiophysical parameter useful as indicative of the current or aspredictive of the future brain state of the patient; and

II) computing means configured to:

(a) continuously sample and process each of the acquired signals; and

(b) display to a user on a monitor information a selected subset of theacquired parameters, said selected subset of parameters which isdisplayed being selected either by system software embodying expertanalytical rules as the most significant parameters or as parametershaving values indicative or predictive at any time of actual orpotential deterioration of the brain state of the patient, with saidparameters being displayed against a scale or scales or in a way whichhighlights to a clinician any variations of the parameters indicative orpredictive of the deterioration of the brain state of the patient, oralternatively being override selected at any time by the user.

In broad terms in a further aspect the invention comprises a method foridentifying, monitoring, and guiding the application of brain therapiesto patients with evolving brain injuries, comprising acquiring amultiple number of signals each indicative of a different biochemical orbiophysical parameter of a patient, and via computing means continuouslysampling each of the acquired signals and displaying to a user on amonitor at least some of the parameters, the displayed parameters beingselected by system software embodying expert analytical rules asparameters having values indicative or predictive at any time of actualor potential future deterioration of the brain state of the patient,with said parameters being displayed against a scale or scales or in away which highlights to a clinician variations of the parametersindicative or predictive of deterioration in the brain state of thepatient.

The brain rescue instrument monitors at least some of thepathophysiologic and temporal events surrounding encephalopathies—whichevents are predictive of pathological neuronal death or can influencethe degree of secondary injury. This information is a prerequisite todeciding whether or not intervention with neuronal rescue therapy isindicated. The invention enables a better detection procedure forpredicting the secondary loss of brain cells, so that steps to alleviatesecondary injury may be taken as soon as possible and even before theappearance of clinical signs, to achieve increased survival and betterlong-term prospects of patients.

BRIEF DESCRIPTION OF THE FIGURES

The invention will be further described with reference to theaccompanying drawings in which:

FIG. 1 is a view of a preferred form trolley mounted brain rescuemonitor of the invention,

FIG. 2 shows an overview of the hardware and software systems of thepreferred from brain rescue monitor,

FIGS. 3 and 4 show screen displays of the preferred form brain rescuemonitor,

FIG. 5 shows preferred EEG electrode placement for use with thepreferred form brain rescue monitor.

FIGS. 6(a) to (e) are graphs of a series of cortical temperaturetreatment profiles following hypoxia,

FIGS. 7(a) to (e) graphically show examples of effects of long termtemperature trends on outcome.

FIG. 8 graphically shows cytotoxic activity as sensed by microdialysis,against time,

FIG. 9 graphically shows examples of the T/QRS ratio from an ECG afterinjury,

FIGS. 10(a) and (b) graphically show seizure and spike activity afterinjury, overtime,

FIGS. 11(a)-(c) illustrate relationships between EEG parameters andoutcome,

FIGS. 12(a) and (b) are tables which correlate blood pressure and otherfactors, vs neuronal outcome,

FIG. 13 graphically relates the duration of ischemia to neuronal loss inspecific areas of the brain,

FIG. 14 graphically illustrates cytotoxic activity as levels ofcitrulline (a marker of nitric oxide activity) and as cortical impedance(CT) vs time,

FIG. 15 graphically shows by example the effect of growth factor(rhIGF-1) rescue therapy on pathophysiology,

FIG. 16 diagramatically shows the phases of brain injury.

FIGS. 17(a) to (c) graphically show an example of the effect of MK801, aNMDA antagonist, on seizures and outcome,

FIG. 18 shows a further set of curves relating cerebral impedance (CI),perfusion (tHb), cytochrome oxidase (Cyt02), and EEG intensity, to time,

FIG. 19 is a table which correlates cortical neuronal loss versusperfusion,

FIG. 20 graphically shows the time course of global cerebral blood flowfollowing hypoxic-ischemic injury (p<0.05),

FIGS. 21(a)-(d) graphically show the time course of changes in parietalcortex extracellular lactate, glucose, ECoG intensity and corticalimpedance that occurs during and for 3 days following a 30 minutehypoxic-ischemic injury (p<0.05)

DETAILED DESCRIPTION OF PREFERRED FORM

The preferred form brain rescue monitor samples, processes, datareduces, stores and evaluates various biochemical and biophysicalparameters of relevance to the management of an individual patient withbrain injury. The system comprises system software embodying expertanalytical rules for managing signal handling and for signal analysis.The system displays information on some of those which are monitored,which are those most significant for the patient type and/or injurytype, against a scale in a way which highlights any variations in theparameters indicative or predictive of deterioration in the brain stateof the patient. The system monitors other input signals in background,and provides an indication to the user if any of those backgroundsignals or parameters varies to indicate a deterioration of the brainstate of the patient. The indication may be by a pop up window whichdisplays information concerning the previously background parameter, orother warning to the user. The collection of all of the information maybe used by a physician in the monitoring and management of braininjuries and guiding the application of brain rescue therapies.

The system hardware of the preferred form brain rescue monitor comprisesan embedded microprocessor with associated data acquisition stages towhich electrodes or sensors connected to the patient, otherinstrumentation, or any other signal sources are connected. A screendisplays information on selected monitored parameters.

Referring to FIG. 1, the preferred form brain rescue monitor unit 1 iscarried on a rolling stand 2 having an internal pneumatic spring whichallows the unit 1 to be adjusted at to different heights at a patient'sbedside, for example. A battery 3 is, in the preferred form, mounted tothe base of the stand as shown, either as the primary power source forthe unit or as a back up to mains power to ensure reliable operation. Inalternative forms the unit may be wall mounted, otherwise bedsidemounted, or even formed as a smaller unit which is attached to thepatient's head or body for example.

FIG. 2 shows the major components of the preferred form system. Thepreferred form system has input channels and data acquisitionelectronics for an EEG signal, an ECG signal, a cortical impedancesignal, cerebral and core temperature signals, arterial blood pressureand arterial oxygen saturation signals, an intracranial pressure signal,cerebral blood flow, cerebral blood volume, cerebral oxygenation andcerebral metabolic signals, systemic glucose concentration and centralglucose concentration signals, a cerebrovascular status signal, centralcytochrome levels, heart rate, central cytotoxic activity, patientmovement or muscle activity. A number of these input signals such asEEG, ECG, cortical impedance, intracranial pressure, near infraredspectroscopy, microdialysis analyses and temperature sensors areobtained as is known in the art via sensors attached to or within thepatient's head. A number of parameters can be sensed through EEGelectrodes such as the EEG itself, seizure and spike activity, andcerebral impedance, and an ECG. In some cases, data for one inputparameter can be extracted from input data on one or a number of otherinput parameters, eg heart rate can be extracted from blood pressure,ECG, and pulse oximetery. In general, sensors used to obtain inputsignals may include fiberoptic leads, tubes, biosensors, pressuretransducers, dialysis probes, flow transducers, thermistors and movementsensors for example. In FIG. 2, a patient's cranium is indicated at 100,and a set of EEG leads are shown at 101 as an example of an input signalsource. Leads 102 and 103 also attached to the patient's scalp indicateother input signal sources.

The input signals are filtered as necessary, amplified andanalogue-to-digital converted where necessary, and optionallymultiplexed together, as indicated by block 104, and passed to databuffer 105. Other input parameter data from other instruments forexample or other data sources may optionally also be input to databuffer 105.

The digitised input signals data may also be compressed and stored. Datacompression may involve averaging or time-to-frequency domainconversion. Standard computer-compatible data storage devices with astandard system for file naming and configuration are utilised. Thesystem is capable of carrying out data reduction, feature extraction, orcompression, of incoming signals of a variety of types. For example, EEGspectra and ECG waveform data are averaged. In particular, conversion ofan EEG, for example, from the time domain to the frequency domain priorto storage can result in a substantial reduction of data, as doesrecording of its mean intensity. Data reduction is a common consequenceof median and/or other forms of filtering.

At block 107 the expert system software embodying expert analyticalrules represented by block 108 is applied to the current and the storeddata for the patient being monitored. The expert system rules aredeveloped from accumulated experimental and clinical experience, asdescribed subsequently. The system continuously samples and analyseseach of the input channels, at a rate appropriate to the input channel.The expert software system may be considered as a number of brain rescuetask instruments indicating various parameters from the input data. Ineither case the software system is configured to display at least someof the parameters being monitored, either selected by the expertsoftware system as the most appropriate to display to the clinician forthe particular patient case, or a combination of parameters which isoverride selected by the clinician. The parameters which are normallydisplayed in the foreground for the particular patient case are thosethat together increase the ability to predict the outcome, or identifythe phase of injury, or guide the selection and/or the application of atherapy to the patient. The software continues to monitor thenon-displayed parameters in background and if any of these is consideredby the expert software system to be such as to indicate a deteriorationof the brain state of the patient, the software causes the previouslybackground parameters) to be displayed, by a pop up window showing theparameter value graphically for example, or causes a warning to be givento the user in some other way via an appearing icon or similar,optionally accompanied by an audible alarm if appropriate.

FIG. 2 also comprises a dataflow diagram and illustrates that digitalsignals are fed continuously into input data buffer 105, subsequentlythe bulk of the data flow is through the signal analytical modules 106,and then through the expert brain rescue task modules 107, and to thedisplay, or data storage device(s). The signal analytical modulesperform artefact rejection, signal processing and analysis, and datareduction. The expert brain rescue task modules then select informationfrom these modules and process the information to aid specific brainrescue tasks. The brain rescue task modules select the pertinentbiophysical measures to display and set the normal and pathologicaldisplay ranges and data display modes and display scales.

For the foreground parameters the display normally shows the most recentperiod of data collection, and highlighted on the display, for eachbiochemical-or biophysical parameter, are any points where there is atleast a suspicion of pathophysiologic levels, or the optimal range forthe biochemical or biophysical parameter that can influence outcome. Forexample, a line or series of points graphically illustrating a monitoredparameter can be displayed in green where the corresponding parameter isclearly within a normal range, or in yellow, and then red for valuesthat the expert system predicts to be unsafe or dangerous. A monochromedisplay may use brighter or flashing lines or points. Display scales maybe non-linear particularly in the display of spectra or wherelogarithmic displays are already accepted. The display may also benon-linear in the time axis if this can be portrayed without riskingconfusion. Alternatively different windows on a screen may displayshort-term events or long-term events respectively.

User interaction with and control of the system in the preferred formsystem is via a touch sensitive screen but may alternatively be via atouch panel or keypad 109 (see FIG. 2), on the front face of thepreferred form instrument for example, a keyboard and/or a mouse, aseparate hand held infra-red unit, or other convenient form of inputdevice.

The unit may include a printer port 113 or a built-in printer, or anetwork interface.

Both short-term events (of the order of 4 seconds) and long-term events(of the order of hours or days) are resolved, evaluated, and displayed.The sampling rates used are capable of resolving brief events and alsoof separating a real, brief event from an artefactual single or seriesof false values, and the unit is capable of storing and recalling of anyor all records over a period of for example 3 days or more. Suchartefacts and interference from the input parameters may be minimisedvia one or more hardware or software filters, and/or via expert rules inthe software applied at the signal processing stage indicated by block106 capable of rejecting events not in accordance with the time scale ofthe signal being recorded. For example, EEG recordings become unreliablewith increased electrode impedance and/or amplifier saturation and/orpresence of movement artefact, and one sign of movement artefact israpid fluctuations in the shape of the waveform. A preferred softwarefilter is a median filter which tends to reject extreme values such asthose resulting from a switching transient coupled to the body.

The system is so far as possible is capable of assessing theeffectiveness of sensor connections and informing the user of any signalchannels that appear to be incorrect. The system monitors each signalline in order to confirm that each channel continues to provide reliableresults because (for example) attached electrodes can be detached orlose effectiveness in other ways. In the event of a problem thecorresponding data is disregarded and a warning message is generated.FIG. 5 shows a display screen of the preferred form brain rescue monitorwhich illustrates the preferred EEG electrode placement, and which mayalso indicate to the user any detached or ineffective electrode. Thesystem will also calibrate itself, as far as possible, so that readingsare quantitative. This means that they have a greater reliability andsignificance to an expert system.

FIG. 3 shows a screen display of the preferred form brain rescuemonitor. Information relevant to specific brain rescue tasks or for themonitoring or management of brain injuries is displayed on the screen(see text and observational data). The information to be displayed isselected by the user via the menus such as the brain rescue task menudisplayed along the bottom left of the screen. In this example timetrend information describing pathophysiologic, cytotoxic and physiologicprocesses are displayed graphically in the upper left region. Incomingsignals are monitored in the upper right region and current patientstatus information is displayed in the panel on the right. The user mayalso mark events, access the help information or alter the settings ofthe machine via the menus in the lower right corner of the screen. Theuser also can alter the information displayed within specific regions byaccessing the associated menus.

FIG. 4 shows another screen display of the preferred form brain rescuemonitor for the evaluation and analysis of historical and/or dataremotely recorded by the brain rescue monitor. The user can select theinformation to be displayed, zoom, scroll, take measurements, filter,process or print or extract information as required via the menus.

More generally in relation to system alarms, the expert system may givea warning to the user when an alarm limit for any parameter is exceeded,by an alarm tone graded according to severity, a visual alarm messagecolour coded according to severity or by flashing a visual alarm messagefor a particular parameter, for example. Alarms can be indefinitelysuspended for 1, 2 or 3 minutes, after which the alarm willautomatically reactivate. In the preferred form unit to prevent unwantedalarms, the parameters which will trigger an alarm may be entered by theclinician. Alarms may be graded and prioritised for example as redalarms to indicate a critical situation occurring; yellow alarms toalert clinicians when alarm limits are exceeded; and technical alarmswhich are triggered by signal quality noise and problems, and equipmentmalfunction.

Optionally the system may make available expert advice having an inbuiltability to predict outcome and/or to identify the pathological processestaking place through an advisor/help system. Some of the rules by meansof which this can be set up are evident from the following observationalevidence, and an expert system for indicating an appropriate responsemay be based on a set of rules, and/or on fuzzy logic (such as numericalweighting of observations), and/or neural networks, and/or analyticalmodels, a combination of those, or those plus additional computationalabilities. The system may also make available representative examples ofpathophysiologic reactions which can be called up by a usercontemplating the case under study. Representative case studies mayassist users to interpret findings, and may assist expert system inmaking its findings.

The software system applies an expert system of rules or expertanalytical models to the signals so that the stage of evolution of headinjury can be identified; the trends in the evolution of the case arerecognised; cytotoxic processes can be identified; a likely outcome canbe determined; and therapy can be recommended, particularly if sometreatable and dangerous condition such as epileptiform activity (whichmay not result in motor activity) is identified.

The parameters which can be usefully monitored in any case may bededucted from the observational evidence disclosed below but specificexamples of brain rescue tasks and the corresponding pathophysiologic,cytotoxic and physiologic responses that can be usefully monitoredinclude:

Patient selection for rescue therapy: eg selection of infants who havesuffered an asphyxial episode for neuronal rescue therapy. Thebiophysical signals monitored includes measures of some of the followingpathophysiologic and cytotoxic processes:

Comprised cortical electrical activity eg loss of EEG intensity and/oramplitude and/or frequency.

Presence of cardiovascular injury eg presence of hypotension and/orchanges within the ST segment of the electrocardiogram.

Presence of cerebral mitochondrial dysfunction or altered metabolism: egincreased cerebral lactate production and/or reduced cerebral oxygenconsumption.

Altered cerebrovascular tone eg increased cerebral blood flow and/orblood volume or decreased cerebral blood flow and/or blood volume.

Patient rejection criteria can include some of the following:

Presence of normal EEG activity eg EEG intensity and/or amplitude and/orfrequency within normal range.

Evidence of persistent cytotoxic edema eg persistently elevated braintissue impedance.

Evidence of brain death eg persistent loss of brain blood flow.

Postasphyxial seizure detection and management: eg for identifying andguiding therapy of those suffering from postasphyxial seizures. Therapymay be either anticonvulsant or antiexcitotoxic agents. The biophysicalsignals monitored includes measures of some of the followingpathophysiologic and cytotoxic processes:

Cortical seizure activity eg presence of seizure activity on the EEGsignal.

Level of background EEG activity eg EEG intensity and/or amplitudeand/or frequency.

Spatial distribution of some of above EEG parameters eg derived from EEGsignals recorded at multiple sites.

Cytotoxic edema eg presence of increased brain tissue impedance.

Excitotoxic activity eg presence of increased glutamate in the braincerebrospinal fluid and/or extracellular fluid.

Compromised cerebral metabolism eg reduced cerebral oxygen consumptionand/or increased cerebral lactate production and/or lactate levels incerebrospinal fluid.

Presence of hyperaemia eg increased cerebral blood flow.

Synchronous increases in blood pressure and/or heart rate, and/or bloodflow and/or muscle activity.

Increases in core and/or cerebral temperature.

Monitoring of electrophysiologic signal validity: Signals to bemonitored may include some of the following:

Range of electrode impedance.

Level of mains hum.

Presence of amplifier clipping.

Presence of input amplifier saturation.

Level of movement artefact.

Application of therapeutic hypothermia: The biophysical signalsmonitored includes measures of some of the following physiologic andpathophysiologic processes:

Core, cerebral and related temperatures:

These temperatures are referred against an optimal temperature rangethat depends on the protocol for example: term infants may be cooled toa core temperature of about 35° C. and adults 33° C.

Duration of cooling for example about 12-72 h post injury.

Rate of progressive rewarming eg about 1° C. per hour.

Heat transfer device(s) temperature status and heat flux(es).

Metabolic or cardiovascular compromise eg systemic lactate levels and/orhypotension.

Pathophysiologic or cytotoxic processes influenced by the hypothermiasuch as cytotoxia edema, vasogenic edema, excitotoxicity, or cerebrallactate production.

Maintenance of optimal status to minimise delayed neoronal injury: Thebiophysical signals monitored includes measures of the levels of some ofthe following physiologic and pathophysiologic processes:

Glucose levels eg serum levels and/or cerebrospinal fluid levels.

Core and/or cerebral temperature.

Blood pressure eg above a minimal hypotensive) level.

Cerebral oxygenation eg measured by near infrared spectroscopy.

Cerebral perfusion eg measured by ultrasonic methods.

Intracranial pressure eg measured by intracerebral pressure sensors.

Presence of seizures eg detected on the EEG signals.

Observational Evidence

The following comprises observations for particular biophysicalparameters. By appropriate weighing of each parameter an expert systemfor many cases can be produced capable of correctly assessing the likelypatient outcome, of indicating the need for specific treatment (such asanti-seizure treatment, seizures seem to immediately precede secondaryneuronal death), and of indicating the progress. The brain rescuemonitor enables the amount of data assessed to exceed that which anindividual clinician can adequately comprehend.

Cerebral electrical activity—EEG: Referring to FIGS. 10, 11, 12 and 18,prolonged depression of EEG activity after injury is predictive ofneuronal loss. Hypothermia or rescue therapies should be initiated inthe depression phase, and a depressed EEG is associated with increasedsusceptibility to further injuries. Recovery of normal activity isassociated with good outcome.

Patient seizure activity (detected via EEG electrodes): Referring toFIG. 10 and FIGS. 8, 14 and 18 linking EEG activity to impedance,seizure activity after injury is predictive of neuronal loss, prolongedcortical seizure activity is predictive of cortical infarction, seizureactivity and/or rise in impedance is associated with excitotoxicity (seelater for details of impedance), seizure activity develops concomitantlywith the secondary rise in impedance, seizure activity occurring withlowering of frequency predicts neuronal loss, synchronous increases EMGactivity or rises in blood pressure or cerebral impedance are associatedwith severe seizures, Seizure activity is suppressed during effectivetherapy with antiexcitotoxic or anticonvulsant (FIG. 17) agents, and EEGdepression before the onset of spike and/or seizure activity isassociated with poor outcome (FIGS. 11, 12(b) and 18). Intermittentseizure activity superimposed on normal EEG activity is associated withstriatal injury (FIG. 10).

Patient spike activity (detected via EEG electrodes): Referring to FIGS.10 and 17, spike activity (bursts of rapid waves) is predictive ofneuronal loss, spike activity often precedes seizure activity, and spikeactivity after depressed EEG and/or rise in cerebral impedance ispredictive of neuronal loss. Spike activity superimposed on normal EEGactivity is associated with striatal injury, and it is useful for thesystem to raise an immediate alarm if spike injury is detected (FIG.10). The effect of administering MK801 is illustrated in FIG. 17; wherethe cortical impedance trace shows a much reduced rise.

Cerebral impedance (detected via EEG electrodes): Referring to FIGS. 8,14, 15 and 18, rising impedance is associated with tissue energyfailure, cytotoxic edema, rising impedance and EEG depression isassociated with tissue energy failure, rising impedance and ischemia isassociated with tissue energy failure, a reversible increase inimpedance predicts delayed damage, and an acute rise in impedancepredicts increased susceptibility to further injuries. (Gangliosidetherapy can be used to counteract against increased susceptibility.)Irreversible acute risk in impedance predicts infarction, increasedimpedance is associated with accumulation of excitotoxins (FIGS. 8, 14,17), prolonged secondary rise in impedance is associated with infarctionand edema, gradually rising impedance and seizure activity is associatedwith the development of an infarct, prolonged large rise in impedanceand loss of electrical activity is associated with brain death, a risein impedance associated with the secondary phase of injury is associatedwith neuronal loss, falling impedance after a prolonged rise isassociated with infarction, falling impedance and resolution of seizureactivity or loss of EEG activity is associated with infarction, regionalchanges in impedance are associated with the location of injury, andcerebral impedance is influenced by temperature. Repetitive increases inimpedance are associated with striatal injury. One example ofalleviation of the signs of cerebral impedance changes is given in FIG.15, where varying amounts of the growth factor rhIGF-1 (or vehiclealone) were given to ovine foetuses at about two hours after ischemia.There are a number of other possible treatments.

Cerebral haemodynamic status: Referring to FIGS. 18 and 20, loss ofcerebral oxygenation is associated with injury: The duration of primaryhyperaemia (increased blood flow and/or blood volume) is predictive ofpoor outcome, the onset time of secondary hyperaemia is predictive ofseverity, secondary hyperaemia precedes edema and/or seizures, andhyperaemia increases during seizures and/or edema. Episodes of venousdesaturation are associated with poor outcome.

Cerebrovascular status: Referring to FIGS. 18, 19 and 20, impairedautoregulation is associated with poor outcome, and regional changes arepredictive of outcome.

Cerebral blood flow: Referring to FIGS. 19 and 20, impaired cerebralblood flow is associated with injury, and increases in cerebral bloodflow are associated with cerebral seizure activity and delayed injury.The degree of hypoperfusion during the immediate reperfusion period andan inverse relationship with the magnitude of delayed hyperperfusion arepredictive of the severity of neuronal loss (FIG. 12b). Reactivehyperaemia occurs during the delayed phase of cell death after injuryand may protect marginally viable tissue (FIGS. 18 and 20).

Cytotoxic activity: Referring to FIGS. 8 and 14, a rise in extracellularcitrulline, a by product of nitric oxide, is associated with delayedinjury. Excitotoxins, such as glutamate, accumulate during the laterphases of injury (FIGS. 8 and 17). Increased levels of cytotoxins areassociated with poor outcome.

Lactate status: Referring to FIG. 21, Increased production of lactate, amarker for mitochondrial damage, is associated with the early phase ofinjury. Elevation in lactate levels are associated with the delayedphase of injury.

Glucose status: Referring to FIG. 21, an elevation in glucose isassociated with the delayed phase of injury. Both hypoglycaemia andhyperglycaemia can worsen brain injury.

Spatial distribution: Referring to FIG. 13, spatial distributions ofcerebral pathophysiologic processes are monitored because spatialchanges are associated with the location of pathophysiologic processeseg changes in EEG can be used to localise changes.

ECG: Referring to FIGS. 9 and 12, the occurrence of ST changes afterasphyxia is predictive of neuronal loss, T wave changes after asphyxiais predictive of neuronal loss, and acute changes in T/QRS ratio areassociated with cerebral injury.

Temperature: Referring to FIGS. 6 and 7, preferably at least core,tympanic and scalp temperature are monitored. Hyperthermia exacerbatesinjury until cerebral function has fully recovered, while prolongedhypothermia suppresses neuronal death, scalp temperature influencescortical damage, and core temperature influences damage in deeper brainstructures.

Arterial blood pressure is monitored, because hypertension increases therisk of injury: Referring to FIG. 12 cerebral perfusion pressure ismonitored because low cerebral perfusion pressure increases risk ofinjury, secondary rise in impedance precedes brain swelling, anddevelopment of hyperaemia then rising impedance predicts brain swelling(FIG. 18).

The foregoing describes the invention including a preferred formthereof. Alterations and modifications as will be obvious to thoseskilled in the art are incorporated in the scope of the invention, asdefined in the following claims.

What is claimed is:
 1. A brain rescue instrument for use in identifying,monitoring, and guiding the application of brain therapies to patientsat risk of secondary phase brain damage including delayed neuronaldeath, comprising: input means for acquiring a group of signals eachindicative of a different biochemical or biophysical parameter of apatient and the behavior of which group of signals over time isindicative or predictive of developing secondary phase damage or a riskthereof, computing means configured to continuously process and displayto a user the acquired signals or information obtained therefrom on oneor more time scales which show variations in the signals which areindicative or predictive of secondary phase brain damage or a risk ofsecondary phase damage, and wherein said group of signals includes anEEG signal or signals and one or more of: a signal or signals indicativeof brain edema, a signal or signals indicative of seizures, a signal orsignals indicative of one or more of core body temperature, cerebraltemperature, and scalp or skin temperature.
 2. A brain rescue instrumentaccording to claim 1 wherein said EEG signals comprise signals from theboth left and right hemispheres.
 3. A brain rescue instrument accordingto claim 2 wherein said computing means is arranged to apply to at leastsome of the signals or information obtained therefrom expert analyticalrules based on knowledge of the behavior of the signals over time duringdeveloping secondary phase brain damage, and to display to a user thesignals or information obtained therefrom in a way which highlightsvariations identified by application of said expert analytical ruleswhich are indicative or predictive of secondary phase brain damage or arisk of secondary phase damage.
 4. A brain rescue instrument accordingto claim 1 wherein said signal or signals indicative of brain edemainclude one or more of a signal indicative of brain tissue impedance, asignal indicative of cytotoxic edema, a signal indicative of vasogenicedema, a signal indicative of intracranial pressure, and a signalindicative of cerebral perfusion pressure.
 5. A brain rescue instrumentaccording to claim 1 wherein said group of signals further includes oneor more of: an ECG signal, a signal indicative of cerebral lactatelevel(s), a signal indicative of cerebral oxygen consumption, a signalor signals obtained from the EEG signal(s) indicative of one or both ofseizure and spike activity, a signal or signals indicative of brainedema, a signal indicative of cerebrovascular status, a signalindicative of cerebral hemorrhage, a signal indicative of cerebral bloodflow, and a signal indicative of blood pressure.
 6. A brain rescueinstrument according to claim 5 wherein said signal or signalsindicative of brain edema include one or both of a signal indicative ofbrain tissue impedance and a signal indicative of cytotoxic edema.
 7. Abrain rescue instrument according to claim 5 arranged to highlightvariations in at least some of the displayed signals or informationwhich are indicative or predictive of secondary phase brain damage.
 8. Abrain rescue instrument according to claim 5 wherein said computingmeans is arranged to apply to at least some of the signals orinformation obtained therefrom expert analytical rules based onknowledge of the behavior of the signals over time during developingsecondary phase brain damage, and to display to a user the signals orinformation obtained therefrom in a way which highlights variationsidentified by application of said expert analytical rules which areindicative or predictive of secondary phase brain damage or a risk ofsecondary phase damage.
 9. A brain rescue instrument according to claim1 wherein said group of signals further includes a signal indicative ofheat transfer device function; and a signal or signals indicative of oneor both of brain edema and cardiovascular compromise.
 10. A brain rescueinstrument according to claim 9 wherein said signal or signalsindicative of brain edema include one or more of a signal indicative ofbrain tissue impedance, a signal indicative of cytotoxic edema, a signalindicative of vasogenic edema, a signal indicative of intracranialpressure, and a signal indicative of cerebral perfusion pressure.
 11. Abrain rescue instrument according to claim 9 wherein said signal orsignals indicative of cardiovascular compromise include one or more ofan ECG signal, a signal indicative of blood pressure, and a signalindicative of systemic lactate level(s).
 12. A brain rescue instrumentaccording to claim 9 arranged to highlight variations in at least someof the displayed signals or information which are indicative orpredictive of secondary phase brain damage.
 13. A brain rescueinstrument according to claim 9 wherein said computing means is arrangedto apply to at least some of the signals or information obtainedtherefrom expert analytical rules based on knowledge of the behavior ofthe signals over time during developing secondary phase brain damage,and to display to a user the signals or information obtained therefromin a way which highlights variations identified by application of saidexpert analytical rules which are indicative or predictive of secondaryphase brain damage or a risk of secondary phase damage.
 14. A brainrescue instrument according to claim 1 wherein said group of signalsfurther includes a signal or signals obtained from the EEG signal orsignals indicative of one or both of seizure and spike activity; and asignal indicative of one or more of: cerebral oxygenation, bloodpressure, cerebral blood flow, systemic glucose level(s), cerebralhemorrhage, cerebral lactate level(s), cerebral glucose level(s), andcytotoxic edema.
 15. A brain rescue instrument according to claim 14wherein said signal or signals indicative of brain edema include one ormore of a signal indicative of brain tissue impedance, a signalindicative of cytotoxic edema, a signal indicative of vasogenic edema, asignal indicative of intracranial pressure, and a signal indicative ofcerebral perfusion pressure.
 16. A brain rescue instrument according toclaim 14 arranged to highlight variations in at least some of thedisplayed signals or information which are indicative or predictive ofsecondary phase brain damage.
 17. A brain rescue instrument according toclaim 14 wherein said computing means is arranged to apply to at leastsome of the signals or information obtained therefrom expert analyticalrules based on knowledge of the behavior of the signals over time duringdeveloping secondary phase brain damage, and to display to a user thesignals or information obtained therefrom in a way which highlightsvariations identified by application of said expert analytical ruleswhich are indicative or predictive of secondary phase brain damage or arisk of secondary phase damage.
 18. A brain rescue instrument accordingto claim 1 wherein said group of signals further includes a signalindicative of one or more of: cerebral haemodynamic status,cerebrovascular status, and excitotoxic activity.
 19. A brain rescueinstrument according to claim 18 wherein said signal or signalsindicative of brain edema include one or more of a signal indicative ofbrain tissue impedance, a signal indicative of cytotoxic edema, a signalindicative of vasogenic edema, a signal indicative of intracranialpressure, and a signal indicative of cerebral perfusion pressure.
 20. Abrain rescue instrument according to claim 1 wherein said group ofsignals further includes one or more signals obtained from the EEGsignal or signals indicative of one or both of seizure and spikeactivity; and a signal or signals indicative of one or more of: cerebraloxygenation, blood pressure, cerebral blood flow, systemic glucoselevel(s), cerebral hemorrhage, cerebral lactate level(s), cerebralglucose level(s), cytotoxic edema, and excitotoxic activity.
 21. A brainrescue instrument according to claim 20 wherein said signal or signalsindicative of brain edema include one or more of a signal indicative ofbrain tissue impedance, a signal indicative of cytotoxic edema, a signalindicative of vasogenic edema, a signal indicative of intracranialpressure, and a signal indicative of cerebral perfusion pressure.
 22. Abrain rescue instrument according to claim 1 arranged to highlightvariations in at least some of the displayed signals or informationwhich are indicative or predictive of secondary phase brain damage. 23.A brain rescue instrument according to claim 1 wherein said computingmeans is arranged to apply to at least some of the signals orinformation obtained therefrom expert analytical rules based onknowledge of the behavior of the signals over time during developingsecondary phase brain damage, and to display to a user the signals orinformation obtained therefrom in a way which highlights variationsidentified by application of said expert analytical rules which areindicative or predictive of secondary phase brain damage or a risk ofsecondary phase damage.
 24. A brain rescue instrument according to claim23 wherein said computing means includes software including signalanalysis modules arranged to perform initial signal processing and brainrescue task modules arranged to apply said expert analytical rules todata from the signal analysis modules.
 25. An intelligent brain rescueinstrument according to claim 23 wherein in applying said expertanalytical rules said computing means is arranged to compare one or moreof said signals or information obtained from said signal(s) againststored information on normal range(s) for said signal(s), and theinstrument is arranged to provide an indication to a user if one or moreof said signal(s) exceeds said normal range(s).
 26. A brain rescueinstrument according to claim 23 wherein in applying said expertanalytical rules said computing means is arranged to compare at leastone combination of more than one signal or information obtained fromsaid signal(s) against stored information on normal ranges for thecombination(s) of signals, and the instrument is arranged to provide anindication to a user if the combination(s) of signals exceeds saidnormal range(s).
 27. A brain rescue instrument according to claim 23wherein in applying said expert analytical rules said computing means isarranged to apply multiple evaluation processes to at least some of thesignals.
 28. A brain rescue instrument according to claim 23 wherein inapplying said expert analytical rules said computing means is arrangedto compare one or more signal(s) acquired from a patient or informationobtained from said signal(s) to signals previously acquired from thesame patient or information obtained therefrom.
 29. A brain rescueinstrument according to claim 23 arranged to store at least some of saidsignals or information acquired from a patient over a number of hours ordays and to apply said expert analytical rules to said stored signals orinformation to identify variations in said signals occurring over anumber of hours or days.
 30. A brain rescue instrument according toclaim 23 arranged to apply said expert analytical rules to storedinformation acquired from a patient over time and to provide anindication to a user of a likely neural outcome for the patient.
 31. Abrain rescue instrument according to claim 1 arranged to store at leastsome of said signals or information obtained from at least some of saidsignals, acquired from a patient over a number of hours.
 32. A brainrescue instrument according to claim 1 arranged to store at least someof said signals or information obtained from at least some of saidsignals, acquired from a patient over one or more days.
 33. A brainrescue instrument according to claim 1 including a software basedadvisor or help system arranged to provide expert advice based on rulesor models in the software to assist a clinician.
 34. A brain rescueinstrument according to claim 1 including stored representative examplesof variations of signals or combinations or groups of signals indicativeor predictive of secondary phase brain damage, which may be called up bya user.
 35. A brain rescue instrument according to claim 1 useful in thedetection of signals or information likely to be erroneous, wherein saidgroup of signals includes one or more of: a signal or signals indicativeof abnormally low signal amplitude, a signal or signals indicative ofabnormally high signal amplitude, a signal or signals indicative ofamplifier clipping, a signal or signals indicative of the presence ofelectrical interference, a signal or signals indicative of artefactinformation, a signal or signals indicative of electrode impedance, asignal or signals indicative of mains hum.
 36. A brain rescue instrumentaccording to claim 1 wherein said computing means and said input meansoccur at the same physical or geographical location.
 37. A brain rescueinstrument according to claim 1 wherein said computing means and saidinput means occur at different physical or geographical locations. 38.Computer means according to claim 1 wherein the processing of saidacquired signals or information obtained from input means and display ofsaid acquired signals or information to a user occurs at differentphysical or geographical locations.
 39. A brain rescue instrument usefulin the detection and management of post insult seizures in patientscomprising input means for acquiring a group of signals each indicativeof a different biochemical or biophysical parameter of a patient and thebehavior of which group of signals over time is indicative or predictiveof developing secondary phase damage or a risk thereof and computingmeans configured to continuously process and display to a user theacquired signals or information obtained therefrom on one or more timescales which show variations in the signals which are indicative orpredictive of secondary phase brain damage or a risk of secondary phasedamage, wherein said group of signals includes an EEG signal or signals;a signal or signals obtained from the EEG signal indicative of one ormore of (i) one or both of cortical seizure and spike activity, (ii) thelevel and frequency of background EEG activity, and (iii) the spatialdistribution of EEG derived signals; and a signal or signals indicativeof one or more of: movement, muscle activity or artefact, heart rate,blood pressure, cerebral blood flow, cerebral haemodynamic status, brainedema, one or more of core body temperature, cerebral temperature, andscalp or skin temperature.
 40. A brain rescue instrument according toclaim 39 wherein said signal or signals indicative of brain edemainclude one or more of a signal indicative of brain tissue impedance anda signal indicative of cytotoxic edema.
 41. A brain rescue instrumentaccording to claim 39 arranged to highlight variations in at least someof the displayed signals or information which are indicative orpredictive of secondary phase brain damage.
 42. A brain rescueinstrument according to claim 39 wherein said computing means isarranged to apply to at least some of the signals or informationobtained therefrom expert analytical rules based on knowledge of thebehavior of the signals over time during developing secondary phasebrain damage, and to display to a user the signals or informationobtained therefrom in a way which highlights variations identified byapplication of said expert analytical rules which are indicative orpredictive of secondary phase brain damage or a risk of secondary phasedamage.
 43. A brain rescue instrument for use in identifying,monitoring, and guiding the application of brain therapies to patientsat risk of secondary phase brain damage including delayed neuronaldeath, comprising: input means for acquiring a number of signals eachindicative of a different biochemical or biophysical parameter of apatient, selection means enabling a user to view groups of said signals,the behavior of each group of signals over time being indicative orpredictive of developing secondary phase damage or a risk thereof, andcomputing means configured to continuously process and display to a userthe selected group of signals or information obtained therefrom on oneor more time scales which show variations in the selected signals whichare indicative or predictive of secondary phase brain damage or a riskof secondary phase damage.
 44. A brain rescue instrument according toclaim 43 wherein said groups of signals comprise two or more groups ofsignals selected from: (I) a group of signals useful in early predictionof risk of secondary damage, that can aid in the selection of patientsfor rescue therapy, including an EEG signal or signals and one or moreof: an ECG signal, a signal indicative of cerebral lactate level(s), asignal indicative of cerebral oxygen consumption, a signal or signalsobtained from the EEG signal(s) indicative of one or both of seizure andspike activity, a signal indicative of brain edema, a signal indicativeof cerebrovascular status, a signal indicative of cerebral haemodynamicstatus, a signal indicative of cerebral hemorrhage, a signal indicativeof cerebral blood flow, and a signal indicative of blood pressure; (II)a group of signals useful in the detection and management of post insultseizures in patients, including an EEG signal or signals; signalsobtained from the EEG signal or signals indicative of one or more of (i)one or both of cortical seizure and spike activity, (ii) the level andfrequency of background EEG activity, and (iii) the spatial distributionof EEG derived signals; and a signal or signals indicative of one ormore of: movement, muscle activity or artefact, heart rate, bloodpressure, cerebral blood flow, cerebral haemodynamic status, brainedema, one or more of core body temperature, cerebral temperature, andscalp or skin temperature; (III) a group of signals useful in patientmonitoring during hypothermia therapy, including an EEG signal orsignals; a signal or signals indicative of one or more core bodytemperature; cerebral temperature, and scalp or skin temperature; asignal indicative of heat transfer device function; and a signal orsignals indicative of one or more of brain edema and cardiovascularcompromise; and (IV) a group of signals useful in monitoring the brainstatus of patients for signs or secondary phase damage or a risk thereofincluding an EEG signal or signals; a signal or signals obtained fromthe EEG signal or signals indicative of one or both of seizure and spikeactivity; a signal or signals indicative of one or more of core bodytemperature, cerebral temperature, and scalp or skin temperature; asignal indicative of brain edema; and a signal indicative of one or moreof: cerebral oxygenation, blood pressure, cerebral blood flow, systemicglucose level(s), cerebral hemorrhage, cerebral lactate level(s),cerebral glucose, and cytotoxic edema. (V) a group of signals useful inmonitoring the brain status of the evolving or secondary phases orneural injury of patients, including an EEG signal or signals; one ormore signals obtained from the EEG signal or signals indicative of oneor both of seizure and spike activity; a signal indicative of brainedema; and a signal indicative of one or more of: cerebral oxygenation,cerebral blood flow, cerebral haemodynamic status, cerebrovascularstatus, cerebral hemorrhage, cerebral lactate level(s), cytotoxic edema,cerebral glucose level(s), excitotoxic activity. (VI) a group of signalsuseful in monitoring to predict risk of secondary phase damage to assistwith minimization of delayed damage, including an EEG signal or signals;one or more signals obtained from the EEG signal or signals indicativeof one or both of seizure and spike activity; a signal indicative of oneor more of core body temperature, cerebral temperature, and scalp orskin temperature; a signal indicative of brain edema; and a signal orsignals indicative of one or more of: cerebral oxygenation, bloodpressure, cerebral blood flow, systemic glucose level(s), cerebralhemorrhage, cerebral lactate level(s), cerebral glucose level(s),cytotoxic edema, and excitotoxic activity.
 45. A brain rescue instrumentaccording to claim 44 wherein said signal or signals indicative of brainedema include one or more of a signal indicative of brain tissueimpedance, a signal indicative of cytotoxic edema, a signal indicativeof vasogenic edema, a signal indicative of intracranial pressure, and asignal indicative of cerebral perfusion pressure.
 46. A brain rescueinstrument according to claim 44, arranged to highlight variations in atleast some of the displayed signals of the selected group which areindicative or predictive of secondary phase brain damage.
 47. A brainrescue instrument according to claim 44 wherein said computing means isarranged to apply to at least some of the signals or informationobtained therefrom expert analytical rules based on knowledge of thebehavior of the signals over time during developing secondary phasebrain damage, and to display to a user the signals or informationobtained therefrom in a way which highlights variations identified byapplication of said expert analytical rules which are indicative orpredictive of secondary phase brain damage or a risk of secondary phasedamage.
 48. A brain rescue instrument according to claim 43, arranged tohighlight variations in at least some of the displayed signals of theselected group which are indicative or predictive of secondary phasebrain damage.
 49. A brain rescue instrument according to claim 43wherein said computing means is arranged to apply to at least some ofthe signals or information obtained therefrom expert analytical rulesbased on knowledge of the behavior of the signals over time duringdeveloping secondary phase brain damage, and to display to a user thesignals or information obtained therefrom in a way which highlightsvariations identified by application of said expert analytical ruleswhich are indicative or predictive of secondary phase brain damage or arisk of secondary phase damage.